Image2Flow: A proof-of-concept hybrid image and graph convolutional neural network for rapid patient-specific pulmonary artery segmentation and CFD flow field calculation from 3D cardiac MRI data.

Computational fluid dynamics (CFD) can be used for non-invasive evaluation of hemodynamics. However, its routine use is limited by labor-intensive manual segmentation, CFD mesh creation, and time-consuming simulation. This study aims to train a deep learning model to both generate patient-specific volume-meshes of the pulmonary artery from 3D cardiac MRI data and directly estimate CFD flow fields. This proof-of-concept study used 135 3D cardiac MRIs from both a public and private dataset. The pulmonary arteries in the MRIs were manually segmented and converted into volume-meshes. CFD simulations were performed on ground truth meshes and interpolated onto point-point correspondent meshes to create the ground truth dataset. The dataset was split 110/10/15 for training, validation, and testing. Image2Flow, a hybrid image and graph convolutional neural network, was trained to transform a pulmonary artery template to patient-specific anatomy and CFD values, taking a specific inlet velocity as an additional input. Image2Flow was evaluated in terms of segmentation, and the accuracy of predicted CFD was assessed using node-wise comparisons. In addition, the ability of Image2Flow to respond to increasing inlet velocities was also evaluated. Image2Flow achieved excellent segmentation accuracy with a median Dice score of 0.91 (IQR: 0.86-0.92). The median node-wise normalized absolute error for pressure and velocity magnitude was 11.75% (IQR: 9.60-15.30%) and 9.90% (IQR: 8.47-11.90), respectively. Image2Flow also showed an expected response to increased inlet velocities with increasing pressure and velocity values. This proof-of-concept study has shown that it is possible to simultaneously perform patient-specific volume-mesh based segmentation and pressure and flow field estimation using Image2Flow. Image2Flow completes segmentation and CFD in ~330ms, which is ~5000 times faster than manual methods, making it more feasible in a clinical environment.

Extended period of ventilation before delayed cord clamping augments left-to-right shunting and decreases systemic perfusion at birth in preterm lambs.

Previous studies have suggested that an extended period of ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. However, it is unknown whether this greater rise in PA flow is accompanied by increases in left ventricular (LV) output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale (FO), with decreased systemic arterial perfusion. Using an established preterm lamb birth transition model, this study compared the effect of a short (∼40 s, n = 11), moderate (∼2 min, n = 11) or extended (∼5 min, n = 12) period of initial mechanical lung ventilation before DCC on flow probe-derived perinatal changes in PA flow, LV output, total systemic arterial blood flow, ductal shunting and FO shunting. The LV output was relatively stable during initial ventilation but increased after DCC, with similar responses in all groups. Systemic arterial flow patterns displayed only minor differences during brief and moderate periods of initial ventilation and were similar after DCC. However, an increase in PA flow was augmented with an extended initial ventilation (P < 0.001), owing to an earlier onset of left-to-right ductal and FO shunting (P < 0.001), and was accompanied by a pronounced reduction in total systemic arterial flow (P = 0.005) that persisted for 4 min after DCC (P ≤ 0.039). These findings suggest that, owing to increased left-to-right shunting and a greater reduction in systemic arterial perfusion, an extended period of ventilation before DCC does not result in greater perinatal circulatory benefits than shorter periods of initial ventilation in the birth transition. KEY POINTS: Previous studies suggest that an extended period of initial ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. It is unknown whether this greater rise in PA flow is accompanied by an increased left ventricular output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale, with decreased systemic arterial perfusion. Anaesthetized preterm fetal lambs instrumented with central arterial flow probes underwent a brief (∼40 s), moderate (∼2 min) or extended (∼5 min) period of ventilation before DCC. Perinatal changes in left ventricular output were similar in all groups, but extended initial ventilation augmented both perinatal increases in PA flow, owing to earlier onset and greater left-to-right ductal and foramen ovale shunting, and perinatal reductions in total systemic arterial perfusion. Extended ventilation before DCC does not confer a greater perinatal circulatory benefit than shorter periods of initial ventilation.

Role of hemolysis on pulmonary arterial compliance and right ventricular systolic function after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB. METHODS: This is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014-2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB. RESULTS: PAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (-0.28 ml/mmHg, 95%CI -0.49 to -0.01, p = 0.012) and RVFI (0.14 mmHg*L-1*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments. CONCLUSION: PAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

A comparison of hemodynamic measurement methods during orthotopic liver transplantation: evaluating agreement and trending ability of PiCCO versus pulmonary artery catheter techniques.

BACKGROUND: Significant hemodynamic changes occur during liver transplantation, emphasizing the importance of precious and continuous monitoring of cardiac output, cardiac index, and other parameters. Although the monitoring of cardiac output by pulse indicator continuous cardiac output (PiCCO) was statistically homogeneous compared to the clinical gold standard pulmonary artery catheterization (PAC) in previous studies of liver transplantation, there are fewer statistical methods for the assessment of its conclusions, and a lack of comparisons of other hemodynamic parameters (e.g., SVRI, systemic vascular resistance index). Some studies have also concluded that the agreement between PiCCO and PAC is not good enough. Overall, there are no uniform conclusions regarding the agreement between PiCCO and PAC in previous studies. This study evaluates the agreement and trending ability of relevant hemodynamic parameters obtained with PiCCO compared to the clinical gold standard PAC from multiple perspectives, employing various statistical methods. METHODS: Fifty-two liver transplantation patients were included. Cardiac output (CO), cardiac index (CI), SVRI and stroke volume index (SVI) values were monitored at eight time points using both PiCCO and PAC. The results were analyzed by Bland-Altman analysis, Passing-bablok regression, intra-class correlation coefficient (ICC), 4-quadrant plot, polar plot, and trend interchangeability method (TIM). RESULTS: The Bland-Altman analysis revealed high percentage errors for PiCCO: 54.06% for CO, 52.70% for CI, 62.18% for SVRI, and 51.97% for SVI, indicating poor accuracy. While Passing-Bablok plots showed favorable agreement for SVRI overall and during various phases, the agreement for other parameters was less satisfactory. The ICC results confirmed good overall agreement between the two devices across most parameters, except for SVRI during the new liver phase, which showed poor agreement. Additionally, four-quadrant and polar plot analyses indicated that all agreement rate values fell below the clinically acceptable threshold of over 90%, and all angular deviation values exceeded ± 5°, demonstrating that PiCCO is unable to meet the acceptable trends. Using the TIM, the interchangeability rates were found to be quite low: 20% for CO and CI, 16% for SVRI, and 13% for SVI. CONCLUSIONS: Our study revealed notable disparities in absolute values of CO, CI, SVRI and SVI between PiCCO and PAC in intraoperative liver transplant settings, notably during the neohepatic phase where errors were particularly pronounced. Consequently, these findings highlight the need for careful consideration of PiCCO's advantages and disadvantages in liver transplantation scenarios, including its multiple parameters (such as the encompassing extravascular lung water index), against its limited correlation with PAC.

[Study on methods measuring mechanical properties of arterial wall by macroscopic indentation].

Accurately evaluating the local biomechanics of arterial wall is crucial for diagnosing and treating arterial diseases. Indentation measurement can be used to evaluate the local mechanical properties of the artery. However, the effects of the indenter's geometric structure and the analysis theory on measurement results remain uncertain. In this paper, four kinds of indenters were used to measure the pulmonary aorta, the proximal thoracic aorta and the distal thoracic aorta in pigs, and the arterial elastic modulus was calculated by Sneddon and Sirghi theory to explore the influence of the indenter geometry and analysis theory on the measured elastic modulus. The results showed that the arterial elastic modulus measured by cylindrical indenter was lower than that measured by spherical indenter. In addition, compared with the calculated results of Sirghi theory, the Sneddon theory, which does not take adhesion forces in account, resulted in slightly larger elastic modulus values. In conclusion, this study provides parametric support for effective measurement of arterial local mechanical properties by millimeter indentation technique.

An electrochemical nitric oxide generator for in-home inhalation therapy in pulmonary artery hypertension.

BACKGROUND: Inhaled NO is a selective pulmonary vasodilator proven to be therapeutic for patients with pulmonary artery hypertension (PAH). The most common NO delivery system in clinical practice is cylinder-based, but unfortunately limited by its high costs, complicated delivery, and the requirement of an extensive supply chain, leaving vast unmet medical needs globally. METHODS: To address the need for rapid, affordable, and safe production of nitric oxide (NO) for in-home inhalation therapy in patients with PAH. We developed a novel portable device to derive NO from a nitrite complex solution with a copper(II)-ligand catalyst, and further examined its effectiveness in a porcine model of PAH. This model was established by using female Bama miniature pig and induced by monocrotaline (MCT) administration. RESULTS: This generator could rapidly and safely produce therapeutic NO at concentrations ranging from 0 to 100 parts per million (ppm) with the least disproportionated nitrogen dioxide (NO2) and byproducts. It could effectively alleviate pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in piglets with PAH, without causing major physiologic disruptions. CONCLUSIONS: Our electrochemical NO generator is able to produce the desired NO doses for pulmonary vasodilation in a safe and sustainable way, with low costs, which paves the way for its subsequent clinical trials in the patient with PAH and other common cardiopulmonary conditions with a high disease burden around the world.

The mechanical and morphological properties of systemic and pulmonary arteries differ in the Madagascar ground boa, a snake without ventricular pressure separation.

The walls of the mammalian aorta and pulmonary artery are characterized by diverging morphologies and mechanical properties, which have been correlated with high systemic and low pulmonary blood pressure, as a result of intraventricular pressure separation. However, the relationship between intraventricular pressure separation and diverging aortic and pulmonary artery wall morphologies and mechanical characteristics is not understood. The snake cardiovascular system poses a unique model for the study of this relationship, as representatives both with and without intraventricular pressure separation exist. In this study, we performed uniaxial tensile testing on vessel samples taken from the aortas and pulmonary arteries of the Madagascar ground boa, Acrantophis madagascariensis, a species without intraventricular pressure separation. We then compared these morphological and mechanical characteristics with samples from the ball python, Python regius, and the yellow anaconda, Eunectes notaeus - species with and without intraventricular pressure separation, respectively. Our data suggest that although the aortas and pulmonary arteries of A. madagascariensis respond similarly to the same intramural blood pressure, they diverge in morphology, and that this attribute extends to E. notaeus. In contrast, P. regius aortas and pulmonary arteries diverge both morphologically and in terms of their mechanical properties. Our data indicate that intraventricular pressure separation cannot fully explain diverging aortic and pulmonary artery morphologies. Following the law of Laplace, we propose that pulmonary arteries of small luminal diameter represent a mechanism to protect the fragile pulmonary vasculature by reducing the blood volume that passes through, to which genetic factors may contribute more strongly than physiological parameters.

Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor.

Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 µM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

A test-retest multisite reproducibility study of cardiovascular four-dimensional flow MRI without respiratory gating.

AIM: To systematically investigate the multisite reproducibility, test-retest reliability, and observer variability of non-respiratory-gated four-dimensional (4D) flow magnetic resonance imaging (MRI) in the thoracic great vessels for the assessment of blood flow and peak velocity. MATERIALS AND METHODS: Electrocardiogram (ECG)-gated 4D flow MRI data were acquired without respiratory gating in 10 healthy volunteers. To analyse multisite reproducibility, 4D flow was scanned at three different sites using a 3 T GE MRI machine with identical protocols for the group of participants. In addition, to evaluate test-retest reliability, the same volunteers were scanned in each centre during a second visit. Data analysis included calculation of peak systolic velocity and time-resolved and total flow of both the ascending aorta and pulmonary artery. Two observers conducted the above measurements to assess the interobserver variability. RESULTS: Multisite, test-retest, interobserver agreement were good for the calculation of total flow and peak systolic velocity (mean differences <10% of the average flow parameter). CONCLUSION: Non-respiratory-gated 4D MRI-based assessment of aortic and pulmonary blood flow can be performed with good reproducibility. It may facilitate the potential clinical application of this technique.

Aging influences pulmonary artery flow and stiffness in healthy individuals: non-invasive assessment using cardiac MRI.

AIM: To investigate age-related changes of the pulmonary artery (PA) using cardiac magnetic resonance imaging (cMRI) in healthy subjects. MATERIALS AND METHODS: A cross-sectional observational study was conducted on apparently healthy subjects who underwent PA velocity-encoded cMRI. cMRI was used to determine PA stiffness parameters such as PA elasticity, relative area change (PA-RAC) and pulse-wave velocity (PA-PWV), and PA flow parameters by subtracting simultaneous forward flow (FF) and backward flow (BF) velocity across the PA cross-section. Data were presented in five age and sex matched groups. RESULTS: One hundred and fifty subjects (20-70 years, 75 men) met the enrolment criteria. PA elasticity and PA-RAC significantly decreased with age (p<0.001), while PA-PWV, regurgitant volume (Vreg) and backward flow volume (VBF) increased in the elderly (p<0.001). Linear regression analysis indicated that PA elasticity (r=-0.441, p<0.0001) and PA-RAC (r=-0.484, p<0.0001) were indirectly and negatively associated with advancing age, whereas PAmin (r=0.331, p<0.0001), PA-PWV (r=0.490, p<0.0001), VReg (r=0.335, p<0.0001) and VBF (r=0.349, p<0.0001) were directly associated with age. Multivariate analysis indicated that age was independently associated with Vreg and VBF, and the addition of PAmin and PA-PWV marginally increased its predictive capacity. CONCLUSION: Aging significantly increases cMRI-based PA flow and stiffness parameters. These could become relevant markers of subclinical changes of the PA geometry in healthy subjects.

Fetal cardiovascular hemodynamics in type 1 diabetic pregnancies at near-term gestation.

INTRODUCTION: Poor glycemic control in maternal type 1 diabetes mellitus during pregnancy can affect fetal cardiac and placental function. However, studies concerning fetal central hemodynamics have revealed conflicting results. We hypothesized that in pregnancies complicated by maternal type 1 diabetes, fetal cardiovascular and placental hemodynamics are comparable to the control fetuses at near-term gestation. In addition, we investigated the relation between newborn serum biomarkers of cardiac function and fetal cardiovascular and placental hemodynamics. Furthermore, we studied whether maternal diabetes is associated with placental inflammation. MATERIAL AND METHODS: In this prospective case-control study, fetal central and peripheral hemodynamics were assessed by ultrasonography in 33 women with type 1 diabetes and in 67 controls with singleton pregnancies between 34+2 and 40+2 gestational weeks. Newborn umbilical cord serum was collected to analyze cardiac natriuretic peptides (atrial and B-type natriuretic peptides) and troponin T concentrations. Placental tissue samples were obtained for cytokine analyses. RESULTS: Fetal ventricular wall thicknesses were greater and weight-adjusted stroke volumes and cardiac outputs were lower in the type 1 diabetes group than in the control group. Pulsatility in the aortic isthmus and inferior vena cava blood flow velocity waveforms was greater in the type 1 diabetes group fetuses than in the controls. A positive correlation was found between branch pulmonary artery and aortic isthmus pulsatility index values. Umbilical artery pulsatility indices were comparable between the groups. Umbilical cord serum natriuretic peptide and troponin T concentrations were elevated in the type 1 diabetes fetuses. These cardiac biomarkers correlated significantly with cardiovascular hemodynamics. Placental cytokine levels were not different between the groups. CONCLUSIONS: In maternal type 1 diabetes pregnancies, fetal cardiovascular hemodynamics is impaired. Maternal type 1 diabetes does not seem to alter placental vascular impedance or induce placental inflammation.

Prenatal hypoxia affects scaling of blood pressure and arterial wall mechanics in the common snapping turtle, Chelydra serpentina.

In reptiles, exposure to hypoxia during embryonic development affects several cardiovascular parameters. These modifications may impose different mechanical stress to the arterial system, and we speculated that the arterial wall of major outflow vessels would be modified accordingly. Since non-crocodilian reptiles possess a partially divided ventricle, ensuing similar systemic and pulmonary systolic pressures, we investigated how morphological and mechanical properties of segments from the left aortic arch (LAo) and the proximal and distal segments of the left pulmonary artery (LPAp and LPAd, respectively) change as body mass (Mb) increases. Eggs from common snapping turtles, Chelydra serpentina, were incubated under normoxia (21% O2; N21) or hypoxia (10% O2; H10), hatched and maintained in normoxia thereafter. Turtles (0.11-6.85 kg) were cannulated to measure arterial pressures, and an injection of adrenaline was used to increase pressures. Portions of the LAo, LPAp and LPAd were fixed under physiological hydrostatic pressures for histology and mechanical assessment. Arterial pressures increased with Mb for N21 but not for H10. Although mechanical and functional characteristics from the LPAp and LPAd were similar between N21 and H10, wall thickness from LAo did not change with Mb in the H10 group, thus wall stress increased in larger turtles. This indicates that larger H10 turtles probably experience an elevated probability of arterial wall rupture without concomitant changes in the cardiovascular system to prevent it. Finally, collagen content of the LPAp and LAo was smaller than in LPAd, suggesting a more distensible arterial wall could attenuate higher pressures from larger turtles.

Gas exchange calculation may estimate changes in pulmonary blood flow during veno-arterial extracorporeal membrane oxygenation in a porcine model.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is used as rescue therapy for severe cardiopulmonary failure. We tested whether the ratio of CO2 elimination at the lung and the V-A ECMO (V˙co2ECMO/V˙co2Lung) would reflect the ratio of respective blood flows and could be used to estimate changes in pulmonary blood flow (Q˙Lung), i.e., native cardiac output. Four healthy pigs were centrally cannulated for V-A ECMO. We measured blood flows with an ultrasonic flow probe. V˙co2ECMO and V˙co2Lung were calculated from sidestream capnographs under constant pulmonary ventilation during V-A ECMO weaning with changing sweep gas and/or V-A ECMO blood flow. If ventilation-to-perfusion ratio (V˙/Q˙) of V-A ECMO was not 1, the V˙co2ECMO was normalized to V˙/Q˙ = 1 (V˙co2ECMONorm). Changes in pulmonary blood flow were calculated using the relationship between changes in CO2 elimination and V-A ECMO blood flow (Q˙ECMO). Q˙ECMO correlated strongly with V˙co2ECMONorm (r2 0.95-0.99). Q˙Lung correlated well with V˙co2Lung (r2 0.65-0.89, P < = 0.002). Absolute Q˙Lung could not be calculated in a nonsteady state. Calculated pulmonary blood flow changes had a bias of 76 (-266 to 418) mL/min and correlated with measured Q˙Lung (r2 0.974-1.000, P = 0.1 to 0.006) for cumulative ECMO flow reductions. In conclusion, V˙co2 of the lung correlated strongly with pulmonary blood flow. Our model could predict pulmonary blood flow changes within clinically acceptable margins of error. The prediction is made possible with normalization to a V˙/Q˙ of 1 for ECMO. This approach depends on measurements readily available and may allow immediate assessment of the cardiac output response.

Prenatal prediction of neonatal haemodynamic adaptation after maternal hyperoxygenation.

The reactivity of the pulmonary vascular bed to the administration of oxygen is well established in the post-natal circulation. The vasoreactivity demonstrated by the fetal pulmonary artery Doppler waveform in response to maternal hyperoxia has been investigated. We sought to investigate the relationship between the reactivity of the fetal pulmonary arteries to hyperoxia and subsequent neonatal cardiac function in the early newborn period. METHODS: This explorative study with convenience sampling measured pulsatility index (PI), resistance index (RI), acceleration time (AT), and ejection time (ET) from the fetal distal branch pulmonary artery (PA) at baseline and following maternal hyperoxygenation (MH). Oxygen was administered for 10 min at a rate of 12 L/min via a partial non-rebreather mask. A neonatal functional echocardiogram was performed within the first 24 h of life to assess ejection fraction (EF), left ventricular output (LVO), and neonatal pulmonary artery AT (nPAAT). This study was conducted in the Rotunda Hospital, Dublin, Ireland. RESULTS: Forty-six women with a singleton pregnancy greater than or equal to 31 weeks' gestational age were prospectively recruited to the study. The median gestational age was 35 weeks. There was a decrease in fetal PAPI and PARI following MH and an increase in fetal PAAT, leading to an increase in PA AT:ET. Fetuses that responded to hyperoxygenation were more likely to have a higher LVO (135 ± 25 mL/kg/min vs 111 ± 21 mL/kg/min, p < 0.01) and EF (54 ± 9% vs 47 ± 7%,p = 0.03) in the early newborn period than those that did not respond to MH prenatally. These findings were not dependent on left ventricular size or mitral valve (MV) annular diameter but were related to an increased MV inflow. There was no difference in nPAAT. CONCLUSION: These findings indicate a reduction in fetal pulmonary vascular resistance (PVR) and an increase in pulmonary blood flow and left atrial return following MH. The fetal response to hyperoxia reflected an optimal adaptation to postnatal life with rapid reduction in PVR increasing measured cardiac output.

The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction.

AIMS: Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. METHODS AND RESULTS: Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001). CONCLUSION: Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. CLINICAL TRIAL REGISTRATION: NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

Axial pulmonary trunk diameter variations during the cardiac cycle.

PURPOSE: Previous studies have shown a correlation between axial pulmonary trunk diameter (PTD) on chest computed tomography (CT) and pulmonary artery pressure. However, it is not known whether the PTD slices measured on chest CT have been recorded during the systolic or diastolic phase. The aim of this study was to demonstrate the variations in PTD during the cardiac cycle by measuring coronary CT angiography (CCTA) images. METHODS: A retrospective analysis was made of 101 patients who underwent CCTA for coronary artery disease assessment. CCTA images were reconstructed during a full cardiac cycle and measurements were taken of the systolic and diastolic PTD and ascending aorta diameter (AAD) from the same slice by two independent observers. RESULTS: Inter-observer agreement was excellent (intraclass correlation coefficient = 0.99) for all CT measurements. The mean systolic PTD of all patients was 26.3 ± 3.6 mm and the mean diastolic PTD was 22.8 ± 3.2 mm (p < 0.001). The mean difference between systole and diastole was found to be 3.5 ± 1.2 mm for PTD, 1.2 ± 0.7 mm for AAD, and 0.1 ± 0.04 for the PTD/AAD ratio (p values < 0.001). There was no statistical significance of PTD variations according to gender, age, height, weight, body mass index, and body surface area. CONCLUSION: When an increased PTD is detected in a chest CT compared to normal limits or a previous CT scan, this may be the result of the variation in PTD due to the cardiac cycle.

Modeling of Hypervolemia in Pulmonary Circulation in Rats Changes the Structure of NO-Mediated Relaxation of Pulmonary Arteries.

We analyzed the contribution of soluble guanylate cyclase-dependent pathway into NO-mediated relaxation of pulmonary arteries under conditions of high pulmonary blood flow modeled by creation of carotid artery-jugular vein shunt in rats. Inhibitor of soluble guanylate cyclase suppressed NO-donor induced relaxation was lower in rats with shunt, but dilatation in response to phosphodiesterase V inhibitor did not differ in the sham-operated and shunt groups. Thus, the structure of NO-mediated vasodilatation of pulmonary arteries under conditions of hypervolemia of pulmonary circulation was shifted to soluble guanylate cyclase-independent pathways, whereas intracellular soluble guanylate cyclase-dependent mechanisms of dilatation were in general unchanged.

The natural matching of harmonic responses in the pulmonary circulation.

KEY POINTS: The right ventricle of the mammal heart is highly sensitive to the afterload imposed by a combination of the pulmonary circulation and the retrograde contribution of the left heart. Right ventricular afterload can be analysed in terms of pulmonary artery input impedance, which we were able to decompose as the result of the harmonic frequency responses of the pulmonary vessels and the left heart attached in series. Using spectral methods, we found a natural matching between the pulmonary vasculature and the left chambers of the heart. This coupling implies that the upstream transmission of the left heart frequency-response has favourable effects on the pulmonary tree. This physiological mechanism protects the right ventricle against acute changes in preload, and its impairment may be a relevant contribution to right ventricle dysfunction in pulmonary hypertension. ABSTRACT: The right ventricle (RV) of the mammal heart is highly sensitive to the afterload imposed by the pulmonary circulation, and the left heart (LH) retrogradely contributes significantly to this vascular load. Transmission-line theory anticipates that the degree of matching between the frequency responses of the pulmonary vasculature and the LH should modulate the global right haemodynamic burden. We measured simultaneous high-fidelity flow (pulmonary artery) and pressure (pulmonary artery and left atrium) in 18 healthy minipigs under acute haemodynamic interventions. From these data, we decomposed the impedance spectra of the total right-circulation system into the impedance of the pulmonary vessels and the harmonic response of the LH. For frequencies above the first harmonic, total impedance was below the pulmonary impedance during all phases (P < 0.001; pooled phases), demonstrating a favourable effect of the LH harmonic response on RV pulsatile load: the LH harmonic response was responsible for a 20% reduction of pulse pulmonary artery pressure (P < 0.001 vs. a theoretical purely-resistive response) and a 15% increase of pulmonary compliance (P = 0.009). This effect on compliance was highest during acute volume overload. In the normal right circulation, the longitudinal impedance of the pulmonary vasculature is matched to the harmonic response of the LH in a way that efficiently reduces the pulmonary pulsatile vascular load. This source of interaction between the right and left circulations of mammals protects the RV against excessive afterload during acute volume transients and its disruption may be an important contributor to pulmonary hypertension.

The independent effects of hypovolaemia and pulmonary vasoconstriction on ventricular function and exercise capacity during acclimatisation to 3800 m.

KEY POINTS: We sought to determine the isolated and combined influence of hypovolaemia and hypoxic pulmonary vasoconstriction on the decrease in left ventricular (LV) function and maximal exercise capacity observed under hypobaric hypoxia. We performed echocardiography and maximal exercise tests at sea level (344 m), and following 5-10 days at the Barcroft Laboratory (3800 m; White Mountain, California) with and without (i) plasma volume expansion to sea level values and (ii) administration of the pulmonary vasodilatator sildenafil in a double-blinded and placebo-controlled trial. The high altitude-induced reduction in LV filling and ejection was abolished by plasma volume expansion but to a lesser extent by sildenafil administration; however, neither intervention had a positive effect on maximal exercise capacity. Both hypovolaemia and hypoxic pulmonary vasoconstriction play a role in the reduction of LV filling at 3800 m, but the increase in LV filling does not influence exercise capacity at this moderate altitude. ABSTRACT: We aimed to determine the isolated and combined contribution of hypovolaemia and hypoxic pulmonary vasoconstriction in limiting left ventricular (LV) function and exercise capacity under chronic hypoxaemia at high altitude. In a double-blinded, randomised and placebo-controlled design, 12 healthy participants underwent echocardiography at rest and during submaximal exercise before completing a maximal test to exhaustion at sea level (SL; 344 m) and after 5-10 days at 3800 m. Plasma volume was normalised to SL values, and hypoxic pulmonary vasoconstriction was reversed by administration of sildenafil (50 mg) to create four unique experimental conditions that were compared with SL values: high altitude (HA), Plasma Volume Expansion (HA-PVX), Sildenafil (HA-SIL) and Plasma Volume Expansion with Sildenafil (HA-PVX-SIL). High altitude exposure reduced plasma volume by 11% (P < 0.01) and increased pulmonary artery systolic pressure (19.6 ± 4.3 vs. 26.0 ± 5.4, P < 0.001); these differences were abolished by PVX and SIL respectively. LV end-diastolic volume (EDV) and stroke volume (SV) were decreased upon ascent to high altitude, but were comparable to sea level in the HA-PVX trial. LV EDV and SV were also elevated in the HA-SIL and HA-PVX-SIL trials compared to HA, but to a lesser extent. Neither PVX nor SIL had a significant effect on the LV EDV and SV response to exercise, or the maximal oxygen consumption or peak power output. In summary, at 3800 m both hypovolaemia and hypoxic pulmonary vasoconstriction contribute to the decrease in LV filling, but restoring LV filling does not confer an improvement in maximal exercise performance.

Fast relaxation and desensitization of angiotensin II contraction in the pulmonary artery via AT1R and Akt-mediated phosphorylation of muscular eNOS.

Angiotensin II (AngII) triggers a transient contraction of pulmonary arteries (PAs) followed by protracted desensitization. Based on the unconventional eNOS expression in PA smooth muscle cells (PASMCs), we hypothesized that activation of smooth muscle eNOS by AngII might be responsible for fast relaxation and tachyphylaxis. Using dual-wire myograph, mechanically endothelium-denuded rat PA [E(-)PA] showed AngII concentration-dependent transient contractions (ΔTAngII, 95% decay within 1 min), which were abolished by losartan (AT1R antagonist). Neither PD123319 (AT2R antagonist) nor A779 (MasR antagonist) affected ΔTAngII. When the vessels were pretreated with L-NAME (NOS inhibitor), ODQ (guanylate cyclase inhibitor), or KT5823 (PKG inhibitor), ΔTAngII of E(-)PA became larger and sustained, whereas nNOS or iNOS inhibitors had no such effect. Immunoblotting of human PASMCs (hPASMCs) also showed eNOS expression, and AngII treatment induced activating phosphorylations of Ser1177 in eNOS and of Ser473 in Akt (Ser/Thr protein kinase B), an upstream signal of eNOS phosphorylation. In addition, L-NAME co-treatment promoted AngII-induced Ser19 phosphorylation of myosin light chain. In hPASMCs, AngII abolished plasma membrane expression of AT1R, and recovery by washout took more than 1 h. Consistent with the data from hPASMCs, the second application of AngII to E(-)PA did not induce contraction, and significant recovery of ΔTAngII required prolonged washout (> 2 h) in the myography study. L-NAME treatment before the second application facilitated recovery of ΔTAngII. Muscular eNOS plays an auto-inhibitory role in ΔTAngII of PAs. The molecular changes investigated in hPASMCs revealed eNOS phosphorylation and internalization of AT1R by AngII. We propose that the rat PA smooth muscle eNOS-induced lusitropy and slow recovery of AT1R from tachyphylaxis might counterbalance the excessive contractile response to AngII, contributing to the distinctive low-pressure pulmonary circulation.